I-BET151

BET family inhibitor; Inhibits BRD2, BRD3, and BRD4

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BET family inhibitor; Inhibits BRD2, BRD3, and BRD4
From: 381 USD

Overview

I-BET151 is an inhibitor of bromodomain and extra terminal (BET) family proteins. BET proteins recognize acetylated lysine residues via their 2 bromodomains (Gallenkamp et al.). I-BET151 inhibits BRD2, BRD3, and BRD4 with IC₅₀ values of 0.5, 0.25, and 0.79 µM, respectively (Kline et al.; Vidler et al.; Hewings et al.; Dawson et al. 2012).

REPROGRAMMING
· Enhances reprogramming of mouse fibroblasts to neurons, in combination with ISX-9, Forskolin, and CHIR99021 (Li et al.)

CANCER RESEARCH
· Induces early cell cycle arrest and apoptosis in human and mouse MLL-fusion leukemia cell lines by blocking transcription of key genes including BCL2, C-MYC, and CDK6 (Dawson et al. 2011).
Alternative Names:
GSK1210151A
CAS Number:
1300031-49-5
Chemical Formula:
C₂₃H₂₁N₅O₃
Molecular Weight:
415.5 g/mol
Purity:
≥ 98%
Pathway:
Epigenetic
Target:
BET

Scientific Resources

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Educational Materials

(1)

Data and Publications

Publications

(7)
Cell stem cell 2015 AUG

Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons.

Li X et al.

Abstract

Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to textgreater90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron-specific genes. Overall, our findings provide a proof of principle" for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation�
ChemMedChem 2014 MAR

Bromodomains and their pharmacological inhibitors.

Gallenkamp D et al.

Abstract

Over 60 bromodomains belonging to proteins with very different functions have been identified in humans. Several of them interact with acetylated lysine residues, leading to the recruitment and stabilization of protein complexes. The bromodomain and extra-terminal domain (BET) proteins contain tandem bromodomains which bind to acetylated histones and are thereby implicated in a number of DNA-centered processes, including the regulation of gene expression. The recent identification of inhibitors of BET and non-BET bromodomains is one of the few examples in which effective blockade of a protein-protein interaction can be achieved with a small molecule. This has led to major strides in the understanding of the function of bromodomain-containing proteins and their involvement in diseases such as cancer and inflammation. Indeed, BET bromodomain inhibitors are now being clinically evaluated for the treatment of hematological tumors and have also been tested in clinical trials for the relatively rare BRD-NUT midline carcinoma. This review gives an overview of the newest developments in the field, with a focus on the biology of selected bromodomain proteins on the one hand, and on reported pharmacological inhibitors on the other, including recent examples from the patent literature.
Journal of medicinal chemistry 2013 APR

Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.

Hewings DS et al.

Abstract

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.
Journal of medicinal chemistry 2012 SEP

Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites.

Vidler LR et al.

Abstract

Bromodomains are readers of the epigenetic code that specifically bind acetyl-lysine containing recognition sites on proteins. Recently the BET family of bromodomains has been demonstrated to be druggable through the discovery of potent inhibitors, sparking an interest in protein-protein interaction inhibitors that directly target gene transcription. Here, we assess the druggability of diverse members of the bromodomain family using SiteMap and show that there are significant differences in predicted druggability. Furthermore, we trace these differences in druggability back to unique amino acid signatures in the bromodomain acetyl-lysine binding sites. These signatures were then used to generate a new classification of the bromodomain family, visualized as a classification tree. This represents the first analysis of this type for the bromodomain family and can prove useful in the discovery of inhibitors, particularly for anticipating screening hit rates, identifying inhibitors that can be explored for lead hopping approaches, and selecting proteins for selectivity screening.
The New England journal of medicine 2012 AUG

Targeting epigenetic readers in cancer.

Dawson MA et al.

Abstract

STEMCELL TECHNOLOGIES INC.’S QUALITY MANAGEMENT SYSTEM IS CERTIFIED TO ISO 13485. PRODUCTS ARE FOR RESEARCH USE ONLY AND NOT INTENDED FOR HUMAN OR ANIMAL DIAGNOSTIC OR THERAPEUTIC USES UNLESS OTHERWISE STATED.